Modulators of the Human Voltage-Gated Proton Channel Hv1

The voltage-gated proton channel (Hv1) selectively transports protons (H+) across biological membranes in response to membrane potential changes. Hv1 is assembled as a dimer, and unlike most voltage-gated ion channels, it lacks a traditional central pore domain; instead, the voltage-sensing domain (VSD) of each monomer facilitates proton conduction via a hydrogen-bond network. Hv1 is widely expressed in various human cell types (e.g., immune cells, sperm, etc.) including tumor cells. In tumor cells, the accumulation of acidic intermediates generated by glycolysis under hypoxic conditions or ROS production leads to significant cytosolic acidification. Hv1 can remove protons from the cytosol rapidly, contributing to the adaptation of the cells to the tumor microenvironment, which may have significant consequences in tumor cell survival, proliferation, and progression. Therefore, Hv1 may be very promising not only as a tumor marker but also as a potential therapeutic target in oncology. Molecules that modulate the proton flux through Hv1 can be divided into two broad groups: inhibitors and activators. Hv1 inhibitors can be simple ions, small molecules, lipids, and peptides. In contrast, fewer Hv1 activators are known, including albumin, NH29, quercetin, and arachidonic acid. The mechanism of action of some inhibitors is well described, but not all. Hv1 modulation has profound effects on cellular physiology, especially under stress or pathological conditions, like cancer and inflammation. The therapeutic application of selective Hv1 inhibitors or activators could be a very promising strategy in the treatment of several serious diseases.